The invention relates to substituted indoles, pharmaceutical compositions containing such indoles, and their use in treating or preventing diseases or conditions mediated by the Peroxisome Proliferator Activated Receptor-xcex3 (PPAR-xcex3).
Peroxisome Proliferator Activated Receptors (PPARs) belong to the steroid/retinoid receptor superfamily of ligand-activated transcription factors. Willson, et al., Curr. Opin. Chem. Biol., (1997), Vol. 1, pp 235-241. To date, three mammalian PPARs have been identified, namely PPAR-xcex1, PPAR-xcex3, and PPAR-xcex4.
PPARs regulate expression of target genes by binding to DNA response elements as heterodimers with the retinoid X receptor. These DNA response elements have been identified in the regulatory regions of a number of genes encoding proteins involved in lipid metabolism and energy balance. The biological role of the PPARs in the regulation of lipid metabolism and storage has been recently reviewed. Spiegelman, Diabetes, (1998), Vol. 47, pp. 507-514; Schoonjans, et al., Curr. Opin. Lipidol., (1997), Vol. 8, pp 159-166; Brun, et al., Curr. Opin. Lipidol., (1997), Vol. 8, pp 212-218.
Molecules that interact with PPAR-xcex3 may be useful in modulating PPAR-xcex3 mediated processes for the treatment or prevention of various diseases and conditions. For example, essential dietary fatty acids and certain of their eicosanoid metabolites are naturally occurring hormonal ligands for the PPAR-xcex3 receptor, which can promote adipogenesis through activation of the PPAR-xcex3 receptor. Kliewer, et al., Proc. Natl. Acad. Sci. USA, (1997), Vol. 94, pp 4318-4323; Kliewer, et al., Cell, (1995), Vol. 83, pp 813-819. Therefore, molecules that inhibit the adipogenic effects of endogenous PPAR-xcex3 hormones may be useful in the treatment of diseases caused by increased fat accumulation or lipid storage, such as osteoporosis, obesity and acne. Tontonoz, et al., Curr. Opin. Genet. Dev., (1995), Vol. 5, pp 571-576. For example, it has been noted that the thiazolidinedione (TZD) class of PPAR-xcex3 ligands promotes adipogenesis in bone marrow and inhibits expression of markers of the osteoblast phenotype, such as alkaline phosphatase. Paulik, et al., Cell Tissue Res., (1997), Vol. 290, pp 79-87. These effects may lead to low bone mineral density and osteoporosis. Similarly, it is known that TZDs can promote lipid accumulation in sebocytes. Rosenfield, et al., N. Dermatology, (1998), Vol. 196, pp 43-46. These effects may lead to sebocyte differentiation and acne formation. Thus, molecules that block adipogenesis in adipocytes, pre-adipocytes, bone marrow, or sebocytes may have beneficial effects in the treatment of obesity, osteoporosis, or acne.
The PPAR-xcex3 receptor has been found in tissues other than adipose, and it is believed that synthetic PPAR-xcex3 ligands and natural PPAR-xcex3 hormones (natural ligands) may have beneficial effects in many other diseases including cardiovascular disease, inflammation, and cancer. Schoonjans, supra; Ricote, et al., Nature, (1998), Vol. 391, pp 79-82; Mueller, et al., Mol. Cell, (1998), Vol. 1, pp 465-470.
TZD PPAR-xcex3 ligands enhance the actions of insulin in man and reduce circulating glucose levels in rodent models of diabetes. The PPAR-xcex3 receptor is expressed in adipose tissue and plays a pivotal role in the regulation of adipocyte differentiation in vitro. TZD such as rosiglitazone induce adipocyte differentiation in vitro through activation of the PPAR-xcex3 receptor.
Although there are clearly therapeutic uses for PPAR-xcex3 ligands in the treatment of diseases of lipid metabolism and energy balance, it is possible that there will be side effects of these drugs. For example, PPAR-xcex3 ligands that promote adipocyte differentiation in vivo could lead to increased fat accumulation and weight gain. This side effect might offset the beneficial effects of a PPAR-xcex3 ligand in the treatment of diabetes or other diseases where obesity is a risk factor. Spiegelman, supra; Brun, supra.
There is precedent among other member of the steroid/retinoid receptor superfamily that synthetic ligands can be identified which mimic many of the beneficial effects but inhibit some of the detrimental side effects of the natural hormones. McDonnell, Biochem. Soc. Trans., (1998), Vol. 26, pp 54-60. These synthetic ligands have been given various labels, including antagonists, anti-hormones, partial agonists, selective receptor modulators, tissue selective ligands, and others. Katzenellenbogen, et al., Mol. Endocinol., (1996), Vol. 10, pp 119-131. Compounds are needed that will modulate PPAR-xcex3 mediated processes for the treatment or prevention of diseases such as osteoporosis, cancer, etc. without the concommitant side-effects of natural hormones.
The invention provides compounds that modulate PPAR-xcex3 mediated processes, particularly substituted indole compounds, which can act as agonists or antagonists of PPAR-xcex3 and thereby modulate PPAR-xcex3 mediated processes. The invention further provides pharmaceutical compositions containing such compounds. Finally, the invention provides for methods of treating or preventing a PPAR-xcex3 mediated diseases or condition in a mammal by administering a compound of the invention.
The invention relates to compounds of the Formula I: 
wherein
R1 
is R8xe2x80x94R9;
R8 
is selected from alkyl of 1-7 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, (CH2)tS(xe2x95x90O)2, and (CH2)nC(xe2x95x90O);
t
is 1-7;
n
is 0-8;
R9 
is selected from phenyl, cycloalkyl of 3-8 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkenyl of 5-9 carbon atoms, and heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O,
wherein R9 may be substituted with alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, halogen, alkyl of 1-8 carbon atoms, haloalkyl of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, or Qxe2x80x94(CH2)nR10;
Q
is selected from NR33, NH, S and O;
R10 
is selected from cycloalkyl of 3-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkenyl of 5-9 carbon atoms, and heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O;
R33 
is selected from alkyl of 1-8 carbon atoms, alkenyl of 1-8 carbon atoms and alkynyl of 1-8 carbon atoms;
X
is selected from NR33, NH, O, and S;
R2 
is selected from hydrogen, alkyl of 1-8 carbon atoms, haloalkyl of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, and (CH2)nS(xe2x95x90O)2R11;
R11 
is selected from aryl of 5-14 carbon atoms and heteroaryl of 3-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, with the proviso that R11 is not isoxazole,
wherein R11 may be substituted with alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, alkoxy of 1-8 carbon atoms, haloalkyl of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, haloalkoxy of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, or halogen;
R3 
is selected from:
(a) R12xe2x80x94R13, wherein
R12 is selected from alkyl of 1-7 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, and C(xe2x95x90O), and
R13 is selected from cycloalkyl of 3-7 carbon atoms, cycloalkenyl of 5-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, and heterocycloalkenyl of 3-8 carbon atoms and 1-2 hetero atoms selected from N, S and O,
wherein R13 may be substituted with alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, alkoxy of 1-8 carbon atoms, haloalkyl of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, haloalkoxy of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, or halogen; or
(b) cycloalkyl of 3-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, and heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O,
all of which may be substituted with alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, cycloalkyl of 3-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, aryl of 5-14 carbon atoms and heteroaryl of 4-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, or may be spiro fused with cycloalkyl of 3-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, aryl of 5-14 carbon atoms and heteroaryl of 4-8 carbon atoms and 1-2 heteroatoms selected from N, S and O; or
(c) aryl of 5-14 carbon atoms or heteroaryl of 3-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, which are substituted with 1-3 of the following:
(i) Si(CH3)3;
(ii) cycloalkyl of 3-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkenyl of 5-9 carbon atoms, and heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O;
(iii) S(xe2x95x90O)2R14 wherein R14 is selected from cycloalkyl of 3-7 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkenyl of 5-9 carbon atoms, heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, aryl of 5-14 carbon atoms and heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O;
(iv) R15,which combines with R5 to form a radical of the formula xe2x80x94Yxe2x80x94(CH2)txe2x80x94
Yxe2x80x94, wherein Y is selected from NR33, NH, S and O;
(v) C(xe2x95x90O)R16,
wherein R16 is selected from alkyl of 1-8 carbon atoms, cycloalkyl of 3-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkenyl of 5-9 carbon atoms, heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, and Zxe2x80x94R17 
wherein Z is selected from (CH2)n, NH, NR33, O and S,
wherein R17 is selected from cycloalkyl of 3-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkenyl of 5-9 carbon atoms, heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, aryl of 5-14 carbon atoms and heteroaryl of 3-11 carbon atoms and 1-2 heteroatoms selected from N, S and O;
(vi) Zxe2x80x94R18xe2x80x94R19, wherein:
R18 is selected from alkyl of 1-8 carbon atoms, cycloalkyl of 3-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkenyl of 5-9 carbon atoms, heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, aryl of 5-14 carbon atoms, heteroaryl of 3-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, and (CH2)nC(xe2x95x90O), and
R19 is selected from hydrogen, halogen, haloalkyl of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, cycloalkyl of 3-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkenyl of 5-9 carbon atoms, heterocycloalkenyl of 3-8 carbon atoms and 1-2 hetero atoms selected from N, S and O, R20xe2x80x94R21 and Zxe2x80x94R21, and
Z is as defined above, and
R20 is selected from aryl of 5-14 carbon atoms and heteroaryl of 3-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, and
R21 is selected from hydrogen, cycloalkyl of 3-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkenyl of 5-9 carbon atoms, heterocycloalkenyl of 3-8 carbon atoms and 1-2 hetero atoms selected from N, S and O, aryl of 5-14 carbon atoms and heteroaryl of 3-11 carbon atoms and 1-2 heteroatoms selected from N, S and O;
with the proviso that when R3 is furyl, benzofuranyl, benzothienyl, benzoxazolidinyl, benzoxazolyl, benzothiazolydinyl, benzothiazolyl, benzoisothiazolyl, benzopyrazolyl, benzoimidazolyl, benzoimidazolidinyl, benzoisooxazolyl, or benzoxadiazolyl R3 may be unsubstituted, and
with the further proviso that, (1) when R3is aryl or heteroaryl, Z is O or (CH2)n, R18 is (CH2)nC(xe2x95x90O), alkyl, aryl or heteroaryl, and R19 is hydrogen, halogen, haloalkyl or alkyl, or (2) when R3is phenyl or napthyl and R16 is alkyl, one of the following applies:
R5 is other than hydrogen and R23 is other than alkyl or alkenyl,
X is NH and R2 is (CH2)nS(xe2x95x90O)2R11,
R8 is (CH2)nC(xe2x95x90O), (CH2)tS(xe2x95x90O)2, alkenyl or alkynyl,
R9 is substituted with Q(CH2)nR10,
R7 is other than hydrogen, or
R4 is other than hydrogen; and
(d) furyl, benzofuranyl, benzothienyl, benzoxazolidinyl, benzoxazolyl, benzothiazolydinyl, benzothiazolyl, benzoisothiazolyl, benzopyrazolyl, benzoimidazolyl, benzoimidazolidinyl, benzoisooxazolyl, or benzoxadiazolyl, which may be substituted with alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, alkoxy of 1-8 carbon atoms, haloalkyl of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, haloalkoxy of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, or halogen; or
R4 is selected from hydrogen and Exe2x80x94R34xe2x80x94R35, wherein
E is selected from NR33, NH, S and O;
R34 is selected from alkyl of 1-8 carbon atoms, cycloalkyl of 3-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkenyl of 5-9 carbon atoms, and heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O;
R35 is selected from hydrogen, halogen, haloalkyl of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, cycloalkyl of 3-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkenyl of 5-9 carbon atoms, and heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O; and
R33 has the meaning given above;
R5 (1) is selected from:
(a) hydrogen;
(b) (CH2)qCOOH
where q is 1-4
(c) C(xe2x95x90O)R22, wherein R22 is selected from alkyl of 1-8 carbon atoms, cycloalkyl of 3-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkenyl of 5-9 carbon atoms, heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, aryl of 5-14 carbon atoms and heteroaryl of 3-11 carbon atoms and 1-2 heteroatoms selected from N, S and O;
(d) cycloalkyl of 3-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and 0, cycloalkenyl of 5-9 carbon atoms, and heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O;
(e) xe2x80x94(CH2)nxe2x80x94Dxe2x80x94R23, wherein:
(i) D is selected from NR33, NH, S and O, and
(ii) R23 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, C(xe2x95x90O)R24, and (CH2)mR24, wherein
m is 0-4, with the proviso that when R3 is phenyl or napthyl, Z is O, R18 is alkyl and R19 is hydrogen, halogen, haloalkyl or alkyl, m is 1-4,
R24 is selected from cycloalkyl of 3-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkenyl of 5-9 carbon atoms, heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, C(xe2x95x90O)OH, NHR27xe2x80x94R28, NR27xe2x80x94R28, (CH2)nOR27xe2x80x94R28, NHxe2x80x94R29xe2x80x94R30 and R29xe2x80x94R30,
R27 is alkyl of 1-8 carbon atoms,
R28 is selected from hydrogen, cycloalkyl of 3-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkenyl of 5-9 carbon atoms, heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, aryl of 5-14 carbon atoms and heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O,
R29 is selected from cycloalkyl of 3-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkenyl of 5-9 carbon atoms, heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, aryl of 5-14 carbon atoms, and heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, and
R30 is selected from hydrogen, halogen, haloalkyl of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, alkoxy of 1-8 carbon atoms, aryl of 5-14 carbon atoms, heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, and C(xe2x95x90O)OH, or
(2) R 5 combines with R6 to form a radical of formula xe2x80x94Yxe2x80x94(CH2)txe2x80x94Yxe2x80x94, wherein Y is as defined above;
R6 is selected from hydrogen, OH, and Txe2x80x94R18xe2x80x94R19,
wherein T is selected from NR33, NH, S and O and R18, R19 and R33 are as defined above;
R7 is selected from hydrogen, C(xe2x95x90O)R22, (CH2)nxe2x80x94Dxe2x80x94R23, and R31xe2x80x94R32,
wherein D, R22 and R23 are as defined above, and
R31 is selected from alkyl of 1-7 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and C(xe2x95x90O), and
R32 is selected from aryl of 5-14 carbon atoms, heteroaryl of 3-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkyl of 3-9 carbon atoms, cycloalkenyl of 5-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, and heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O,
wherein R32 may be substituted with alkyl of 1-7 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, alkoxy of 1-8 carbon atoms, haloalkyl of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, haloalkoxy of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, or halogen;
and pharmaceutically acceptable salts thereof.
The invention further relates to pharmaceutical compositions containing any of the above-described compounds of Formula I and a pharmaceutically acceptable carrier.
The invention also provides methods for treating or preventing a PPAR-xcex3 mediated disease or condition in a mammal. The PPAR-xcex3 mediated disease or condition may be osteopororsis, osteopenia, PPAR-xcex3 mediated cancer, including breast, prostate, colon and lung cancer, inflammation, including atherosclerosis, inflammatory bowel disease, Alzheimer""s disease and rheumatoid arthritis, hypertension, hyperglycemia, type 1 diabetes, type 2 diabetes, syndrome X, insulin resistance, obesity, dyslipidemia, hypertriglyceridemia, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia, and skin disorders, such as acne, psoriasis, dermatitis, eczema, keratosis and inflammatory skin conditions caused by lupus erythematosus. The methods of the invention provide for the administration of a compound of Formula I or a compound of Formula IIa: 
wherein
R1 
(1) is selected from hydrogen and R8xe2x80x94R9, or
(2) combines with R7 to form a radical of the formula 
R8 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, (CH2)nS(xe2x95x90O)2 and (CH2)nC(xe2x95x90O);
R9 is selected from aryl of 5-14 carbon atoms, heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkyl of 3-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkenyl of 5-9 carbon atoms, and heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O;
wherein R9 may be substitituted with alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, halogen, alkyl of 1-8 carbon atoms, haloalkyl of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, or Xxe2x80x94(CH2)nCH3R10,
R10 is selected from cycloalkyl of 3-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkenyl of 5-9 carbon atoms, heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O;
X and Xxe2x80x2 are each independently selected from NH, NR33, (CH2)n, O and S;
n is a number from 0-8;
R33 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms and alkynyl of 2-8 carbon atoms;
R2 is selected from hydrogen, alkyl of 1-8 carbon atoms, haloalkyl of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, NHS(xe2x95x90O)2R11, and (CH2)nS(xe2x95x90O)2R11;
R11 is selected from aryl of 5-14 carbon atoms and heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O,
wherein R11 may be substituted with alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, alkoxy of 1-8 carbon atoms, haloalkyl of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, or halogen;
R3 is selected from:
(a) hydrogen,
(b) R12xe2x80x94R13, wherein
R12 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and (CH2)nC(xe2x95x90O),
R13 is selected from aryl of 5-14 carbon atoms, heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkyl of 3-9 carbon atoms, cycloalkenyl of 5-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, and heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O,
wherein R13 may be substituted with alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, haloalkyl of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, or halogen;
(c) cycloalkyl of 3-9 carbon atoms, cycloalkenyl of 5-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, heterocycloalkenyl of 3 -8 carbon atoms and 1-2 heteroatoms selected from N, S and O, all of which may be:
(i) substituted with aryl of 5-14 carbon atoms, heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkyl of 3-9 carbon atoms, cycloalkenyl of 5-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, and C(xe2x95x90O)(CH2)nCH3, or
(ii) fused with a spiro ring of 1-6 carbon atoms, or
(iii) fused with an aryl of 5-14 carbon atoms or a heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, either of which may be substituted with alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, haloalkyl of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, or halogen;
(d) aryl of 5-14 carbon atoms or heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, either of which may be substituted with:
(i) xe2x80x94Si(CH3)3;
(ii) S(xe2x95x90O)2R14, wherein R14 is selected from aryl of 5-14 carbon atoms, heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkyl of 3-9 carbon atoms, cycloalkenyl of 5-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, and heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O,
(iii) R15, which combines with R5 to form a radical of the formula xe2x80x94Yxe2x80x94(CH2)nxe2x80x94Yxe2x80x94, wherein Y and n are as defined above;
(iv) C(xe2x95x90O)R16,
wherein R16 is selected from alkyl of 1-8 carbon atoms and Xxe2x80x94R17 
wherein R17 is selected from aryl of 5-14 carbon atoms, heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkyl of 3-9 carbon atoms, cycloalkenyl of 5-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, and heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, and
wherein X is as defined above;
(v) Xxe2x80x94R18xe2x80x94R19 
R18 is selected from alkyl of 1-8 carbon atoms, aryl of 5-14 carbon atoms, heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkyl of 3-9 carbon atoms, cycloalkenyl of 5-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, and heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O,
R19 is selected from hydrogen, halogen, haloalkyl of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, aryl of 5-14 carbon atoms, heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkyl of 3-9 carbon atoms, cycloalkenyl of 5-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, and heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, R20xe2x80x94R21 and Xxe2x80x94R21,
X is as defined above,
R20 is aryl of 5-14 carbon atoms or heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, and
R21 is selected from aryl of 5-14 carbon atoms, heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkyl of 3-9 carbon atoms, cycloalkenyl of 5-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, and heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O,
R4 is selected from hydrogen and Xxe2x80x94R18xe2x80x94R19,
wherein X, R18 and R19 have the meanings given above;
R5 (1) is selected from:
(a) hydrogen;
(b) R12xe2x80x94R13 
wherein R12 and R13 are as defined above,
(c) C(xe2x95x90O)R22, wherein
R22 is selected from alkyl of 1-8 carbon atoms, aryl of 5-14 carbon atoms, heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkyl of 3-9 carbon atoms, cycloalkenyl of 5-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, and heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O,
(d) alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, aryl of 5-14 carbon atoms, heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkyl of 3-9 carbon atoms, cycloalkenyl of 5-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, and heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O,
(e) xe2x80x94(CH2)nxe2x80x94Yxe2x80x94R23, wherein:
(i) Y and n are as defined above,
(ii) R23 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, C(xe2x95x90O)R24, (CH2)nR24, and R25xe2x80x94R26, wherein
R25 is alkyl of 1-8 carbon atoms,
R26 is selected from aryl of 5-14 carbon atoms, heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkyl of 3-9 carbon atoms, cycloalkenyl of 5-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, and heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O,
R24 is selected from cycloalkyl of 3-9 carbon atoms, cycloalkenyl of 5-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, C(xe2x95x90O)OH, NHR27xe2x80x94R28, NR27xe2x80x94R28, NR33R27xe2x80x94R28, (CH2)nR27xe2x80x94R28, and R29xe2x80x94R30,
R27 is alkyl of 1-8 carbon atoms,
R28 is selected from hydrogen, aryl of 5-14 carbon atoms, heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkyl of 3-9 carbon atoms, cycloalkenyl of 5-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, and heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, all of which, with the exception of hydrogen, may be fused with aryl of 5-14 carbon atoms or heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected N, S and O,
R29 is selected from aryl of 5-14 carbon atoms, heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkyl of 3-9 carbon atoms, cycloalkenyl of 5-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, and heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, and
R30 is selected from hydrogen, halogen, haloalkyl of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, aryl of 5-14 carbon atoms and heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O;
(2) combines with R6 to form a radical of the formula xe2x80x94Yxe2x80x94(CH2)nxe2x80x94Yxe2x80x94, wherein Y and n have the meanings given above;
R6 is selected from hydrogen, OH and Xxe2x80x94R18xe2x80x94R19,
wherein X, R18 and R19 have the meanings give above
R7 is selected from hydrogen, C(xe2x95x90O)R22, (CH2)nxe2x80x94Yxe2x80x94R23, and R12xe2x80x94R13,
wherein R22, R23, R12, R13, Y and n have the meanings give above; and pharmaceutically acceptable salts thereof.
The present invention therefore provides compounds, pharmaceutical compositions containing such compounds, and methods for the treatment or prevention of PPAR-xcex3 mediated diseases and conditions. Compounds, compositions and methods of the present invention therefore are useful in treatment of PPAR-xcex3 mediated diseases and conditions without the concommitant undesired side-effects of natural hormones. These and other aspects of the invention will be more apparent from the following description and claims.
The invention provides novel, substituted indoles of Formula I, pharmaceutical compositions containing such indoles, and their use in the treatment or prevention of PPAR-xcex3 mediated diseases or conditions in a mammal. The invention further provides methods of treating or preventing PPAR-xcex3 mediated diseases or conditions in a mammal, such as a human, by administration of a compound of Formula IIa. The compounds of Formula I and Formula IIa have both been broadly described above.
In one embodiment of the compounds of Formula I:
R8 is alkyl
R9 is phenyl, which may or may not be substituted;
X is O;
R2 is hydrogen; and
R3 is aryl, particularly phenyl, or heteroaryl, either of which may or may not be substituted.
As used herein, the term xe2x80x9carylxe2x80x9d includes aromatic ring structures that are substituents on another atom. These aryls may also be substituted with substituents, such as halogen, haloalkyl, alkoxy, haloalkoxy, etc. Non-limiting examples of aryls include phenyl, napthyl, etc. Likewise, the term xe2x80x9cheteroarylxe2x80x9d as used herein includes aromatic ring structures containing between one and two heteroatoms, such as O, N and S, that are substituents on another atom. These heteroaryls may also be substituted with substituents, such as alkyl, alkenyl, alkoxy, haloalkoxy, halogen, haloalkyl, etc. Non-limiting examples of heteroaryls include pyridyl, furyl, quinolyl, etc.
As used herein the term xe2x80x9calkylxe2x80x9d includes straight-chain or branched alkyls of between 1 and 8 carbon atoms. The term xe2x80x9calkenylxe2x80x9d includes straight-chain or branched alkenyls of between 2 and 8 carbon atoms. As used herein the term xe2x80x9calkynylxe2x80x9d includes straight-chain or branched alkynyls of between 2 and 8 carbon atoms. Such alkyls, alkenyls and alkynyls may be terminal or may be linkers between other portions of a molecule.
Examples of compounds of the invention where R3 is a heteroaryl include, but are not limited to: 
Examples of compounds of the invention where R3 is phenyl include, but are not limited to: 
In another embodiment of the invention, R3 is R12xe2x80x94R13, where R13 is cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl. Examples of compounds of the invention where R3 is R12xe2x80x94R13 include, but are not limited to: 
In other embodiments of the invention, R3 is a cycloalkyl, heterocylcoalkyl, cycloalkenyl or heterocycloalkenyl, which may be substituted or may be fused with a spiro ring of 3-9 carbon atoms. Examples of compounds of the invention where R3 is a cycloalkyl, heterocylcoalkyl, cycloalkenyl or heterocycloalkenyl include, but are not limited to: 
In still other embodiments of the invention, R4, R5, R6 and/or R7 may be other than hydrogen. Examples of compounds of the invention where R4, R5, R6 and/or R7 are other than hydrogen include, but are not limited to: 
Compounds of Formulas I and IIa may be useful in the treatment or prevention of PPAR-xcex3 mediated diseases or conditions. An agent which binds to PPAR-xcex3 may be employed for a wide variety of indications, including, but not limited to:
(1) osteoporosis and osteopenia, see, Nuttall, et al., Bone 27 (2), (2000), 177-184; Gimble, et al., Bone 19 (5), (1996), 421-428;
(2) cancer, particularly PPAR-xcex3 mediated cancers, such as breast and prostate cancers (see, Gelman, et al., Cell. and Mol. Life Sci., 55 (6-7), (1999), 935-943; Kersten, et al., Nature, 405 (6785), May 25, 2000, 421-424), colon cancer (see, Saez, et al., Nat. Med., 4 (9) Sept. 1998, 1058-1061; Lefebvre, et al., Nat. Med., 4 (9), Sept. 1998, 1053-1057; Demetri, et al., Proc. Nat""l. Acad. Sci. USA, 96 (7), Mar. 30, 1999, 3951-3956) liposarcoma (Demetri, et al., Proc. Nat""l. Acad. Sci USA, 96 (7), Mar. 30, 1999, 3951-3956) and lung cancer (see, Chang, et al., Cancer Res., 60, 2000, 1129-1138);
(3) hyperglycemia, type 1 diabetes, type 2 diabetes, syndrome X, and insulin resistance, (see Lehmann, et al., J. Bio. Chem., 270 (22) (1995), 12953-12956; Spiegelman, Diabetes, 47 (4), (1998), 507-514);
(4) obesity, (see Zhou, et al., Proc. Nat""l. Ac. Sci. USA, 96 (5), (1999), 2391-2395; U.S. Pat. No. 6,033,656);
(5) inflammation, particularly inflammatory bowel disease (see Cell. and Mol. Life Sci., 55 (6-7), (1999), 935-943), Alzheimer""s disease (see, Combs, et al, J. Neurosci. 20 (2), 2000, 558-567), rheumatoid arthritis (see, Jiang, et al., Nature 391 (6662), 1998, 82-86), and atherosclerosis (see Pasceri, et al., Circulation, 101 (3), 2000, 235-238);
(6) cardiovascular disease, particularly hypertension, (see Cell. and Mol. Life Sci., 55 (6-7), (1999), 935-943 review);
(7) dyslipidemia, hypertriglyceridemia, diabetic dyslipidemia, hyperlipidemia and hypercholesteremia (see Hulin, et al., Curr. Pharm. Design, 2 (1996), 85-102); and
(8) skin disorders, particularly inflammatory skin disorders caused by lupus erythematosus, and acne, psoriasis, dermatitis, eczema and keratosis (see, WO 99/34783; U.S. Pat. No. 5,981,586).
Compounds of Formulas I and IIa are preferably used in the treatment or prevention of osteopenia, osteoporosis, and PPAR-xcex3 mediated cancers, including breast, prostate and colon cancer.
The present invention also includes pharmaceutically acceptable salts of the compounds of Formulas I and IIa. Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic acid, sulphonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. In addition, pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations (e.g., Li+ Na+ or K+), alkaline earth cations (e.g., Mg+2, Ca+2 or Ba+2), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations such as those arising from protonation or peralkylation of triethylamine, N,N-diethylamine, N,N-dicyclohexylamine, pyridine, N,N-dimethylaminopyridine (DMAP), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
A number of the compounds of Formulas I and IIa possess asymmetric carbons and can therefore exist in racemic and optically active forms. Methods of separation of enantiomeric and diastereomeric mixtures are well known to the skilled in the art. The present invention encompasses any racemic or optically active forms of compounds described in Formula I or Formula IIa which possess PPAR-xcex3 modulating activity or the use of any racemic or optically active forms of the compounds described in Formulas I and IIa for the treatment or prevention of PPAR-xcex3 mediated diseases or conditions.
The therapeutic agents of the invention may be employed alone or concurrently with other therapies. For example, when employed as a treatment for osteoporosis or osteopenia, the compounds of the invention may be used in combination with a calcium source, vitamin D or analogues of vitamin D, and/or antiresorptive therapies such as estrogen replacement therapy, treatment with a fluoride source, treatment with calcitonin or a calcitonin analogue, or treatment with a bisphosphonate such as alendronate. The method of the invention is intended to be employed for treatment of PPAR-xcex3 mediated diseases or conditions in both humans and other mammals.
The compounds may be administered orally, dermally, parenterally, by injection, by inhalation or spray, or sublingually, rectally or vaginally in dosage unit formulations. The term xe2x80x9cadministered by injectionxe2x80x9d includes intravenous, intraarticular, intramuscular, subcutaneous and parenteral injections, as well as use of infusion techniques. Dermal administration may include topical application or transdermal administration. One or more compounds may be present in association with one or more non-toxic pharmaceutically acceptable carriers and, if desired, other active ingredients.
Compositions intended for oral use may be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable preparations.
Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. These compounds may also be prepared in solid, rapidly released form.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions containing the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions may also be used. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.
The compounds may also be in the form of non-aqueous liquid formulations, e.g., oily suspensions which may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
The compounds may also be administered in the form of suppositories for rectal or vaginal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug. Such materials include cocoa butter and polyethylene glycols.
Compounds of the invention may also be administered transdermally using methods known to those skilled in the art (see, e.g., Chien; xe2x80x9cTransdermal Controlled Systemic Medicationsxe2x80x9d; Marcel Dekker, Inc.; 1987. Lipp et al. WO 94/04157 Mar. 3, 1994). For example, a solution or suspension of a compound of Formula I or IIa in a suitable volatile solvent optionally containing penetration enhancing agents can be combined with additional additives known to those skilled in the art, such as matrix materials and bacteriocides. After sterilization, the resulting mixture can be formulated following known procedures into dosage forms. In addition, on treatment with emulsifying agents and water, a solution or suspension of a compound of Formula I or Ia may be formulated into a lotion or salve.
Suitable solvents for processing transdermal delivery systems are known to those skilled in the art, and include lower alcohols such as ethanol or isopropyl alcohol, lower ketones such as acetone, lower carboxylic acid esters such as ethyl acetate, polar ethers such as tetrahydrofuran, lower hydrocarbons such as hexane, cyclohexane or benzene, or halogenated hydrocarbons such as dichloromethane, chloroform, trichlorotrifluoroethane, or trichlorofluoroethane. Suitable solvents may also include mixtures one or more materials selected from lower alcohols, lower ketones, lower carboxylic acid esters, polar ethers, lower hydrocarbons, halogenated hydrocarbons.
Suitable penetration enhancing materials for transdermal delivery systems are known to those skilled in the art, and include, for example, monohydroxy or polyhydroxy alcohols such as ethanol, propylene glycol or benzyl alcohol, saturated or unsaturated C8-C18 fatty alcohols such as lauryl alcohol or cetyl alcohol, saturated or unsaturated C8-C18 fatty acids such as stearic acid, saturated or unsaturated fatty esters with up to 24 carbons such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl isobutyl tert-butyl or monoglycerin esters of acetic acid, capronic acid, lauric acid, myristinic acid, stearic acid, or palmitic acid, or diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbons such as diisopropyl adipate, diisobutyl adipate, diisopropyl sebacate, diisopropyl maleate, or diisopropyl fumarate. Additional penetration enhancing materials include phosphatidyl derivatives such as lecithin or cephalin, terpenes, amides, ketones, ureas and their derivatives, and ethers such as dimethyl isosorbid and diethyleneglycol monoethyl ether. Suitable penetration enhancing formulations may also include mixtures one or more materials selected from monohydroxy or polyhydroxy alcohols, saturated or unsaturated C8-C18 fatty alcohols, saturated or unsaturated C8-C18 fatty acids, saturated or unsaturated fatty esters with up to 24 carbons, diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbons, phosphatidyl derivatives, terpenes, amides, ketones, ureas and their derivatives, and ethers.
Suitable binding materials for transdermal delivery systems are known to those skilled in the art and include polyacrylates, silicones, polyurethanes, block polymers, styrene-butadiene coploymers, and natural and synthetic rubbers. Cellulose ethers, derivatized polyethylenes, and silicates may also be used as matrix components. Additional additives, such as viscous resins or oils may be added to increase the viscosity of the matrix.
For all regimens of use disclosed herein for compounds of Formulas I and IIa, the daily oral dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily rectal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/Kg. The daily inhalation dosage regimen will preferably be from 0.01 to 10 mg/Kg of total body weight.
It will be appreciated by those skilled in the art that the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be understood, however, that the specific dose level for any given patient will depend upon a variety of factors, including, but not limited to the activity of the specific compound employed, the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, time of administration, route of administration, rate of excretion, drug combinations, and the severity of the condition undergoing therapy. It will be further appreciated by one skilled in the art that the optimal course of treatment, i.e., the mode of treatment and the daily number of doses of a compound of Formula I or IIa or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.
The compounds of Formulas I and IIa may be prepared by use of known chemical reactions and procedures, from known compounds (or from starting materials which, in turn, are producible from known compounds) through the preparative methods shown below, as well as by other reactions and procedures known to the skilled in the art. Such reactions and procedures include, but are not limited to, esterification, hydrolysis, alkylation, acylation neutralization, coupling, oxidation, reduction, condensation, elimination and substitution reactions. Nevertheless, the following general preparative methods are presented to aid practitioners in synthesizing the compounds of the invention, with more detailed particular examples being presented in the experimental section. The examples are for illustrative purposes only and are not intended, nor should they be construed, to limit the invention in any way.
Within the scope of each method, optional substituents may appear on reagents or intermediates which may act as protecting groups or other non-participating groups. Utilizing methods well known to those skilled in the art, such groups are introduced and/or removed during the course of the synthetic schemes to provide the compounds of the present invention. All variable groups not defined below are as described hereinabove.
In general, compounds of Formula I or IIa may be prepared from the appropriately substituted indoles, by esterification, hydrolysis, sulfonylation or neutralization reactions as shown in Flow Diagram I: 
Preparation of certain Formula I compounds with a variety of R3 substituents may be prepared by a sequence involving conversion of VI to a boronic acid intermediate, followed by a palladium-facilitated coupling reaction with an organohalide and base, such as triethylamine, potassium carbonate or Huenig""s base, as shown in Flow Diagram II. Alternatively, either a boronic acid or organotin intermediate may be coupled with VI under similar conditions. 
Other compounds with heterocycloakenyl or heteroaryl substituents at the R3 position may prepared by condensation of 3-carboxy-substituted indoles with 2-aminoethanols, 2-aminophenols or 2-aminothiols as illustrated in Flow Diagram III. 
Certain aryl substituents on the R3 aryl ring may be further transformed to other substituents by standard means. An illustration of this is shown in Flow Diagram IV, in which a nitro group is reduced and acylated to provide amido substituents. 
Compounds of Formula I which bear certain R3 substituents may be prepared by Friedel-Crafts acylation of the corresponding unsubstituted indole, followed by reduction of the carbonyl group to a methylene, as shown in Flow Diagram V. 
Compounds of Formula I with similar substituents at either R5 or R7 may be likewise prepared, either individually (Flow Diagram VI) or as mixtures (Flow Diagram VII) by an analogous sequence of acylation and reduction reactions. In the latter scheme, where R5 and R7 are hydrogen in the starting materials, individual compounds may be obtained by chromatographic separation of products (Ig and Ii) after the initial step. 
O-Alkylation reactions may be utilized to prepare Formula I compounds bearing substituents on R4, R5, R6 or R7 positions. For example, alkylation of the corresponding hydroxy intermediates provides ethers containing an R18 or R23 group, depending upon position, as shown in Flow Diagram VIII. 
A more detailed example of this process is shown for compounds bearing R5 the group in Flow Diagram IX. 
Other compounds of Formula I may also be obtained from a hydroxy intermediate. For example, the hydroxy group may be converted to a trifluoromethylsulfonate which reacts with an alkyl stannane to give alkyl-substituted indoles, as exemplified in Flow Diagram X for the R5 position. 
Nitration of indoles that are unsubstituted at positions 5 and/or 7 provides nitro-substituted intermediates which may be reduced and either acylated or alkylated to give a variety of Formula I compounds as shown in Flow Diagram XI. 
Indole intermediates which are useful in the preparation of compounds in the present invention are either commercially available or may be prepared by standard methods. These transformations are summarized in Flow Diagram XII for intermediates of Formula VI, IV and V. For example, an appropriately substituted 2-bromonitrobenzene may be converted to a 2-nitrocinnamic acid derivative which cyclizes to an indole upon reduction. The resulting indole intermediate may then be brominated at the 3 position, and the desired R1 substituent introduced by N-alkylation giving the intermediate compounds of Formula VI. Compounds of Formula IV may be prepared from VI in a stepwise sequence involving halogen-metal exchange, addition to formaldehyde, and oxidation of the resulting carbinol to a 3-carboxylic acid. It is understood that the presence of certain R4xe2x80x94R7 substituents may require additional steps of protection and deprotection during this process in order to avoid undesired side reactions. 
The introduction of the carboxyl functionality at position 2 of other indole compounds may be accomplished by a sequence shown in Flow Diagram XIII. The nitrogen of the unsubstituted indole is first protected as a sulfonamide, then subjected to acylation conditions catalyzed by Lewis acid. Protection may be then be removed and the desired R1 attached as described above. 
Examples of preparations of both intermediates and compounds of the invention are provided in the following detailed synthetic procedures. In the tables of compounds to follow, the synthesis of each compound is referenced back to these exemplary preparative steps. All temperatures are reported uncorrected in degrees Celsius (xc2x0 C.). Unless otherwise indicated, all parts and percentages are by volume.
All reactions were performed under a positive pressure of dry argon, and were stirred magnetically unless otherwise indicated. Sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Commercial grade reagents and solvents were used without further purification. Thin-layer chromatography (TLC) was performed on Whatman(copyright) pre-coated, glass-backed silica gel 60A F-254 250 xcexcm plates. Column chromatography (flash chromatography) was performed using 230-400 mesh EM Science(copyright) silica gel. Melting points (mp) were determined using a Thomas-Hoover melting point apparatus, an Electrothermal melting point apparatus, or a Mettler FP66 automated melting point apparatus and are uncorrected.
1H-NMR spectra were recorded with a Varian Mercury (300 MHz,) or a Bruker Avance 500 (500 MHz) spectrometer with either Me4Si (xcex4 0.00) or residual protonated solvent (CDCl3 xcex4 7.26; CD3OD xcex4 3.30; DMSO-D6 xcex4 2.49; Acetone-D6 xcex4 2.04; or CD3CN xcex4 1.94).
HPLCxe2x80x94electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a YMC Pro C18 2.0 mmxc3x9723 mm column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Gradient elution from 90% A to 95% B over 4 minutes was used on the HPLC. Buffer A was 98% water, 2% Acetonitrile and 0.02% TFA. Buffer B was 98% Acetonitrile, 2% water and 0.018% TFA. Spectra were scanned from 140-1200 amu using a variable ion time according to the number of ions in the source.
Fourier transform infrared spectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer.
Elemental analyses were conducted by Robertson Microlit Labs, Madison N.J. NMR mass and infrared spectra, and elemental analyses of the compounds were consistent with the assigned structures.